EP1842555A1 - Mittel zur unterdrückung der toleranzentwicklung für narkotische analgetika - Google Patents

Mittel zur unterdrückung der toleranzentwicklung für narkotische analgetika Download PDF

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Publication number
EP1842555A1
EP1842555A1 EP05820197A EP05820197A EP1842555A1 EP 1842555 A1 EP1842555 A1 EP 1842555A1 EP 05820197 A EP05820197 A EP 05820197A EP 05820197 A EP05820197 A EP 05820197A EP 1842555 A1 EP1842555 A1 EP 1842555A1
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EP
European Patent Office
Prior art keywords
receptor
tolerance
medicament
morphine
analgesic
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Withdrawn
Application number
EP05820197A
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English (en)
French (fr)
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EP1842555A4 (de
Inventor
G. c/o Graduate Sch. Pharmaceut. Sci. TSUJIMOTO
Y. c/o Fukuoka University TAKANO
Kenji c/o Fukuoka University HONDA
Akito c/o N.C.C.H.D. TANOUE
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Japan Health Sciences Foundation
Fukuoka University
Kyoto University NUC
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Japan Health Sciences Foundation
Fukuoka University
Kyoto University NUC
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Application filed by Japan Health Sciences Foundation, Fukuoka University, Kyoto University NUC filed Critical Japan Health Sciences Foundation
Publication of EP1842555A1 publication Critical patent/EP1842555A1/de
Publication of EP1842555A4 publication Critical patent/EP1842555A4/de
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a medicament for suppressing development of tolerance to a narcotic analgesic such as morphine.
  • narcotic analgesics such as morphine have superior analgesic effect on visceral pain and the like, they have been clinically used for pain treatment of patients with terminal cancer.
  • prolonged administration of narcotic analgesics rapidly induces tolerance to the analgesic effect as their primary action. Therefore, careful control of administration frequency and dose thereof is required to minimize the development of tolerance while achieving desired analgesic effect.
  • agents for suppressing development of tolerance to narcotic analgesics for example, medicaments described in International Patent Publication WO97/6139 and the like have been proposed. However, any medicament having superior effectiveness has not yet been clinically developed.
  • Vasopressin is an antidiuretic hormone which is a peptide consisting of nine amino acids. In many mammals including human, the substance exists as arginine vasopressin (AVP) in which the eighth amino acid is arginine.
  • Vasopressin receptors are seven-transmembrane receptors belonging to the G-protein coupled receptor superfamily. As the vasopressin receptors, the V 2 receptor, which promotes the production of cAMP, and the V 1 receptor, which activates phospholipase C, increases the intracellular calcium concentration via release of inositol 1,4,5-trisphosphate and produces diacylglycerol to activate protein kinase C, are known. The V 1 receptor exists in the vascular smooth muscles and causes vasoconstriction via elevation of the intracellular calcium concentration.
  • V 1a and V 1b receptors are also known to exist.
  • the V 1a receptor is known to be involved in the vasoconstrictive action
  • V 1b receptor is known to be involved in secretion of adrenocorticotrpic hormone (ACTH) from the pituitary gland.
  • ACTH adrenocorticotrpic hormone
  • many functions of the V 1b receptor remain unrevealed.
  • no report has been made to date that teaches involvement of the V 1b receptor in the development of tolerance to narcotic analgesics.
  • compounds having an suppressing action on the V 1b receptor those described in International Patent Application Unexamined Publication in Japanese (Kohyo) Nos. 2003-523351 , 2003-523354 , 2003-525287 and 2004-50265 are known.
  • these publications do not suggest or teach that these compounds suppress the development of tolerance to narcotic analgesics.
  • An object of the present invention is to provide a medicament having a suppressing action against development of tolerance to analgesic effect which is induced by administration of a narcotic analgesic such as morphine.
  • the inventors of the present invention conducted various researches to achieve the foregoing object. As a result, they found that, among the vasopressin receptors, the V 1b receptor was involved in the development of tolerance to narcotic analgesics, and antagonists of the V 1b receptor markedly suppressed the development of tolerance to narcotic analgesics.
  • the present invention was accomplished on the basis of the aforementioned findings.
  • the present invention thus provides a medicament for suppressing development of tolerance to analgesic effect of a narcotic analgesic, which comprises an antagonist of vasopressin receptor 1b as an active ingredient.
  • the present invention provides the aforementioned medicament, which is for combination use with a narcotic analgesic.
  • the combination use can be attained by using a single dosage unit containing both of the drugs or separate dosage units each containing either of the drugs as an active ingredient. When the combination use is attained by using separate dosage units, they can be administered simultaneously or at different times.
  • the present invention provides the aforementioned medicament, wherein the narcotic analgesic is morphine hydrochloride or morphine nitrate, preferably morphine hydrochloride.
  • a method for suppressing development of tolerance to analgesic effect of a narcotic analgesic which comprises the step of administering an effective amount of vasopressin receptor 1b to a mammal including human, and use of the vasopressin receptor 1b for the manufacture of the aforementioned medicament.
  • the medicament of the present invention has a suppressing action against development of tolerance to analgesic effect induced by administration of a narcotic analgesic such as morphine, and can reduce or prevent the development of tolerance to analgesic effect of a narcotic analgesic.
  • a narcotic analgesic such as morphine
  • the medicament of the present invention is for suppressing development of tolerance to analgesic effect of a narcotic analgesic, which comprises an antagonist of the vasopressin receptor 1b (hereinafter, referred to as "V 1b receptor") as an active ingredient.
  • V 1b receptor a receptor having affinity for arginine vasopressin is preferred.
  • the antagonist of the V 1b receptor although an antagonist selective to the V 1b receptor is preferably used, a substance that also acts as an antagonist of the V 1a receptor as well as to the V 1b receptor can be used as the active ingredient of the medicament of the present invention.
  • the affinity for the V 1b receptor can be confirmed by, for example, the method of Y. De Keyser et al. (Febs Letters, 356, pp.215-220, 1994 ). Further, the antagonistic action on the V 1b receptor can be confirmed according to, for example, the method of C.S-L., GAL (J. Pharm. Exp. Ther., 300, pp.1122-1130, 2002 ). Any arbitrary substance for which the antagonistic action on the V 1b receptor is confirmed by the aforementioned method can be used as the active ingredient of the medicament of the present invention.
  • the antagonist of the V 1b receptor include the compounds described in International Patent Application Unexamined Publication in Japanese (Kohyo) Nos. 2003-523351 , 2003-523354 , 2003-525287 , 2004-502654 and the like.
  • substances that can be used as the active ingredient of the medicament of the present invention are not limited to those described in the aforementioned publications.
  • the active ingredient of the medicament of the present invention compounds in free forms or physiologically acceptable salts, or hydrates or solvates thereof may be used.
  • Stereoisomers such as optically active substances and diastereomers, arbitrary mixtures of stereoisomers, racemates and the like may also be used as the active ingredient of the medicament of the present invention.
  • the medicament of the present invention can reduce or prevent development of tolerance to analgesic effect of a narcotic analgesic.
  • the medicament of the present invention can be prophylactically used for the purpose of reducing or preventing the development of tolerance.
  • the medicament of the present invention also has an action of reducing or eliminating tolerance to analgesic effect already developed due to administration of a narcotic analgesic. Therefore, the medicament of the present invention can also be therapeutically used for the purpose of reducing or eliminating already developed tolerance, generally with continuously using a narcotic analgesic in combination.
  • the terminology "suppressing development of tolerance" used in the specification is meant to include reduction or elimination of already developed tolerance as described above, and should not be construed in any limitative sense.
  • Types of narcotic analgesics are not particularly limited so long as tolerance to their analgesic effect is substantially developed by a single administration or continuous administration over a short or prolonged period.
  • examples of the narcotic analgesics include morphines obtained from opium and semisynthesized products thereof, non-natural compounds such as pethidine having a morphine-like action and salts thereof, and the like.
  • alkaloids obtained from opium and semisynthesized products thereof, such as phenanthrenes (morphine, oxymorphone, hydromorphone, codeine, hydrocodeine, heroin, thebaine, buprenorphine and the like); phenylpiperidines (meperidine, fentanyl and the like); phenylheptylamines (methadone, propoxyphene and the like); morphinans (levorphanol, methorphan, levorphan and the like); benzomorphans (phenazocine, pentazocine and the like), and the like.
  • phenanthrenes morphine, oxymorphone, hydromorphone, codeine, hydrocodeine, heroin, thebaine, buprenorphine and the like
  • phenylpiperidines meperidine, fentanyl and the like
  • phenylheptylamines metalhadone, propoxyphene and the like
  • morphinans levorphanol, methorphan,
  • examples also include analgesic peptides including endogenous morphine-like substances such as enkephalins (methionine enkephalin, leucine enkephalin); endorphins ( ⁇ -endorphin, ⁇ -endorphin, ⁇ -endorphin); dynorphins (dynorphin A, dynorphin B); proenkephalins as the precursors thereof (proenkephalins, propiomelanocortins, prodynorphins and the like), and the like.
  • enkephalins methionine enkephalin, leucine enkephalin
  • endorphins ⁇ -endorphin, ⁇ -endorphin, ⁇ -endorphin
  • dynorphins dynorphin A, dynorphin B
  • proenkephalins as the precursors thereof (proenkephalins, propiomelanocortins, prodynorphin
  • Administration method of the aforementioned medicament of the present invention is not particularly limited, and it can be orally or parenterally administered to human or mammals other than human depending on the type, dosage form and the like of the active ingredient.
  • a substance that is a V 1b receptor antagonist per se may be used as the medicament of the present invention.
  • the medicament of the present invention can be administered separately from a narcotic analgesic by using a narcotic analgesic which itself is provided in a dosage form of a solution, tablet or the like in combination.
  • a pharmaceutical composition (so-called a combined drug) containing a narcotic analgesic and a V 1b receptor antagonist as the active ingredient of the medicament of the present invention can also be prepared and administered.
  • Methods for the combination use with a narcotic analgesic are not particularly limited.
  • Employable methods include, for example, a method of continuously administering the medicament of the present invention throughout the administration period of a narcotic analgesic; a method of administering the medicament of the present invention as required during the administration period of a narcotic analgesic; a method of starting administration of the medicament of the present invention prior to administration of a narcotic analgesic and then continuing administration of the narcotic analgesic and the medicament of the present invention; a method of continuously administering a narcotic analgesic and the medicament of the present invention, then terminating the administration of the narcotic analgesic and further continuing the administration of the medicament of the present invention alone, and the like.
  • preparations as dosage units suitable for oral administration include tablets, capsules, powders, subtilized granules, granules, solutions, syrups, and the like.
  • preparations as an dosage unit suitable for parenteral administration include injections for subcutaneous, intravenous or intramuscular injection, drip infusions, suppositories, inhalants, transdermal agents, transmucosal agents, patches, and the like.
  • additives for pharmaceutical preparations include excipients, disintegrating agents or disintegrating aids, binders, lubricants, coating agents, dyes, diluents, vehicles, dissolving agents or dissolving aids, isotonic agents, pH modifiers, stabilizers, propellants, tackifiers, and the like. These additives for pharmaceutical preparations are widely used by those skilled in the art, and it should be recognized that suitable additives for pharmaceutical preparations can be selected for a specific dosage form.
  • dose and administration period of the medicament of the present invention are not particularly limited, they can be selected depending on the type and the administration route of the active ingredient, degree of tolerance development, purpose of administration such as prophylactic or therapeutic use, age and body weight of a patient, and the like.
  • the effectively acting concentration of the V 1b receptor antagonist as the active ingredient can be easily confirmed by those skilled in the art by using, for example, the method specifically explained in the following examples.
  • the dose is preferably selected by using the effectively acting concentration as a criterion so that a sufficient blood concentration can be achieved.
  • the dose of the medicament of the present invention may be selected to be in the range of about 0.01 to 10,000 mg/day in terms of the amount of the active ingredient.
  • the medicament of the present invention is repeatedly administered at a large dose, it is desirable to suitably select the dose while monitoring the suppressing action on development of tolerance to analgesic effect. It is preferable to administer the medicament of the present invention as long as possible throughout the administration period of a narcotic analgesic.
  • V 1a receptor knockout mice Neuroscience Letters, 356, pp.195-198, 2004
  • V 1b receptor knockout mice J. Clin. Invest., 113, pp.302-309, 2004
  • control mice body weight: about 30 g
  • s.c. subcutaneously
  • the analgesic effect was evaluated by the tail-flick test on 1st, 5th, 9th, 12th and 15th days after the administration on the basis of the maximal possible effect (%MPE), which represents analgesic intensity and is calculated in accordance with the following equation.
  • %MPE maximal possible effect
  • % MPE 100 ⁇ Measured value after treatment - Measured value before treatment + Cut - off value - Measured value before treatment
  • mice Male ddY mice (5- or 6-week old) were intracerebroventricularly (i.c.v.) given with 5 ⁇ l of physiological saline or a V 1 receptor antagonist (0.5, 5 or 10 ng), and immediately after the administration, the mice were subcutaneously given with 10 mg/kg of morphine hydrochloride, which was repeated twice a day for 5 days to induce tolerance to morphine analgesic.
  • the analgesic effect was evaluated by the tail-flick test on 1st, 3rd and 5th days after the administration on the basis of intensity of analgesic effect using %MPE and AUC (area under the time-reaction curve, Area Under the Curve).
  • the V 1 receptor antagonist the following three types of antagonists were used.
  • mice were given with a solvent (1% DMSO in physiological saline, i.c.v) or a V 1b antagonist (i.c.v.) twice a day (at 9:00 and 17:00) for 4 days.
  • the analgesic effect was determined by the tail-flick test (TailFlick Unit, UgoBasile, Milano, Italy).
  • the analgesic effect of morphine (10 mg/kg, s.c.) was observed after the first administration of morphine on the 1st, 3rd, and 5th days. Intensity of the heat source was set so that the reference reaction time became 2 or 3 seconds.
  • Cut-off time was set to be 10 seconds so that possible damage to the caudal skin was minimized.
  • the analgesic effect was represented in terms of the maximal possible effect (%MPE) for the time lapsed after the administration of morphine (Fig. 5).
  • the intracerebroventricular administration of the V 1b receptor antagonist had no effect on the acute morphine-induced analgesic effect.
  • Fig. 6 shows effect of a V 1b receptor antagonist on the development of tolerance to the morphine-induced analgesic effect.
  • the area under the time-reaction curve (AUC) was obtained using the time lapse shown in Fig. 5.
  • AUC is considered to represent the total analgesic effect level. It was demonstrated that, by intracerebroventricular administration of the V 1b receptor antagonist, the development of tolerance to morphine was successfully suppressed without any effect on the acute morphine-induced analgesic effect.
  • the medicament of the present invention has a suppressing action against development of tolerance to analgesic effect induced by administration of a narcotic analgesic such as morphine, and can reduce or prevent development of tolerance to analgesic effect of a narcotic analgesic.
  • a narcotic analgesic such as morphine

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EP05820197A 2004-12-27 2005-12-26 Mittel zur unterdrückung der toleranzentwicklung für narkotische analgetika Withdrawn EP1842555A4 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004376533 2004-12-27
PCT/JP2005/023783 WO2006070742A1 (ja) 2004-12-27 2005-12-26 麻薬性鎮痛剤の耐性形成抑制剤

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EP1842555A1 true EP1842555A1 (de) 2007-10-10
EP1842555A4 EP1842555A4 (de) 2009-08-19

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EP05820197A Withdrawn EP1842555A4 (de) 2004-12-27 2005-12-26 Mittel zur unterdrückung der toleranzentwicklung für narkotische analgetika

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US (2) US20080227802A1 (de)
EP (1) EP1842555A4 (de)
JP (1) JPWO2006070742A1 (de)
WO (1) WO2006070742A1 (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008071779A1 (en) * 2006-12-13 2008-06-19 N.V. Organon V3 antagonists for the treatment or prevention of chronic pain

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030114683A1 (en) * 2000-01-25 2003-06-19 Richard Roux Novel 1,3-dihydro-2h-indol-2-one derivatives and their use as ligands for v1b and v1a arginine-vasopressin receptors

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Publication number Priority date Publication date Assignee Title
FR2804115B1 (fr) * 2000-01-25 2002-03-08 Sanofi Synthelabo Nouveaux derives de 1,3-dihydro-2h-indol-2-one, un procede pour leur preparation et les compositions pharmaceutiques en contenant
FR2805536B1 (fr) * 2000-02-25 2002-08-23 Sanofi Synthelabo Nouveaux derives de 1,3-dihydro-2h-indol-2-one, un procede pour leur preparation et les compositions pharmaceutiques en contenant
FR2810320B1 (fr) * 2000-06-19 2002-08-23 Sanofi Synthelabo Nouveaux derives de 1,3-dihydro-2h-indol-2-one, un procede pour leur preparation et les compositions pharmaceutiques en contenant
FR2827604B1 (fr) * 2001-07-17 2003-09-19 Sanofi Synthelabo Nouveaux derives de 1-phenylsulfonyl-1,3-dihydro-2h-indol-2- one, un procede pour leur preparation et les compositions pharmaceutiques en contenant

Patent Citations (1)

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US20030114683A1 (en) * 2000-01-25 2003-06-19 Richard Roux Novel 1,3-dihydro-2h-indol-2-one derivatives and their use as ligands for v1b and v1a arginine-vasopressin receptors

Non-Patent Citations (5)

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Title
GUILLON G ET AL: "The discovery of novel vasopressin V1b receptor ligands for pharmacological, functional and structural investigations." JOURNAL OF NEUROENDOCRINOLOGY APR 2004, vol. 16, no. 4, April 2004 (2004-04), pages 356-361, XP002534329 ISSN: 0953-8194 *
See also references of WO2006070742A1 *
TAKAHASHI M ET AL: "Role of arginine vasopressin and its receptor subtypes in the development of morphine tolerance" REGULATORY PEPTIDES, ELSEVIER SCIENCE BV, NL, vol. 53, 21 February 1994 (1994-02-21), pages S205-S206, XP023465883 ISSN: 0167-0115 [retrieved on 1994-02-21] *
TAO P-L ET AL: "The role of vasopressin on the effect of U-50,488 to block the development of morphine tolerance and physical dependence" NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY, SPRINGER, BERLIN, DE, vol. 335, 1 January 1997 (1997-01-01), pages 281-287, XP002995703 ISSN: 0028-1298 *
XU Q ET AL: "Dependency on the brain function of arginine vasopressin system of the development to and recovery from analgesic tolerance to morphine" BRAIN RESEARCH, ELSEVIER, AMSTERDAM, NL, vol. 577, 1 January 1991 (1991-01-01), pages 189-193, XP002995702 ISSN: 0006-8993 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008071779A1 (en) * 2006-12-13 2008-06-19 N.V. Organon V3 antagonists for the treatment or prevention of chronic pain

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US20100004275A1 (en) 2010-01-07
US20080227802A1 (en) 2008-09-18
EP1842555A4 (de) 2009-08-19
WO2006070742A1 (ja) 2006-07-06
JPWO2006070742A1 (ja) 2008-08-07

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